Gastrointestinal (“GI”) function disorders are caused by the invasion of pathogens, post treatment of broad-spectrum antibiotics, improper diet, stressful lifestyle and other causative factors. They are very common diseases, with conditions such as Irritable Bowel Syndrome (IBS) presenting in as much as 20% of the adult population in the USA. In Canada, IBS is second only to the common cold as the leading cause of time absent from school and work. So far, there is no effective medicine for the treatment IBS and Inflammatory Bowel Disease (IBD). Desirably, compositions for therapeutic purposes should meet the following criteria:
Non-toxic, safe to use.
Not inhibiting or adversely affecting probiotic bacteria in the gut.
Preferably very poor oral bioavailability (no systemic effects).
Not causing bacterial resistance.
Anti-inflammatory.
Anti-diarrhea, antisecretory.
Anti-motility.
Strengthening immunity.
Neutralizing toxins.
This invention seeks to provide compositions and treatments for GI functional disorders which meet one or more of the above criteria.
In humans, the gastrointestinal (GI) tract with an area of 300-400 m2 is the second largest surface connecting the body with the outside world. With consumption of 1˜2 kg of food every day, the GI immune system is presented with the threat of ingested poisons and pathogens together with an enormous variety of harmless antigens. The GI tract digests food and absorbs the nutrients that are beneficial to the body, while eliminating components that pose a potential risk to health. A large portion of the body's immune system is located in the GI wall and the mesenteric lymph nodes, called gut-associated lymphoid tissue (GALT) system. GI secretions are rich in antimicrobial factors such as lactoferrin and lysozyme and other factors, like important growth and mucosa healing factors such as epidermal growth factor (EGF). The mucosa of the gut is normally covered by a unique protective layer of mucus and is colonized by microflora, which perform a key function in the regulation of the GALT system.
The mucus serves to a large extent as a matrix for the indigenous protective flora. The intestines contain about 1 kg probiotic bacteria. The roles of these bacteria are to maintain the healthy ecology in the GI tract, synthesizing vitamins, hormones, and other important factors, and to help to break down complex proteins and fiber into smaller molecules that can be absorbed by the mucosal cells.[1]
Pathogenic bacteria in the intestinal tract are an important aspect in the GI functional disorders both as a causative factor and as a symptom. Other disorders can actually cause the GI tract to lose probiotic bacteria and allow pathogenic bacteria growth, eventually, resulting in changes to the intestinal ecology and further exacerbation of the GI functional disorders.
For the treatment of GI functional disorders it is important to restore healthy ecology. This invention relates to the treatment of GI functional disorders and related conditions including IBS and IBD including colitis, Crohn's disease and coeliac disease. The treatment is expected to improve intestinal health and reduce symptoms including constipation, flatulence and diarrhea. It acts as a GI cleanser, strengthening the immune system, inhibiting and removing the pathogenic bacteria, and helping to restore a healthy ecology in the intestinal tract. The resulting healthy digestion system will support the healthy state of the body and healthy weight gain in animals including humans.
Berberine is an isoquinoline quaternary alkaloid derived from a number of species of the barberry plant including Berberis aristata and Coptis chinensis.[2] Structural analogues of berberine have been isolated from extracts of the Chinese medicinal plant, Acangelisia gusanlung.[3] which has been used for over 2000 years in traditional Eastern medicine to treat gastro-enteritis and secretory diarrhea[4] and is also effective in the prevention and the treatment of animal models of diarrhea.[5-7] Berberine possesses antimicrobial[4], anti-motility[8] and anti-secretory properties.[9-11] Thus, several mechanisms may contribute to the therapeutic usefulness of berberine. Berberine has been used as an anti-diarrhea drug at dose range of 100 mg˜300 mg t.i.d. in adult (6 mg˜18 mg/kg/day) in China.[12] Finally the apparent permeability coefficient (Papp) of berberine across the intestinal tissue was of the order of 10−7 cm/s[13], typical of the values of poorly absorbed compounds, and reflected by poor bioavailability in vivo. This poor oral bioavailability causing poor systemic absorptions should offer the benefit of safe use of the oral administration of berberine.
Certain saturated lower dialdehydes also possess antibacterial activity toward sulfate-reducing bacteria.[14] Furthermore, alcoholic sporicidal compositions containing similar saturated lower dialdehydes were taught.[15] Also it is known that water-soluble dialdehyde starch can be incorporated into chewing gum compositions as a cariostatic agent[16], a water insoluble dialdehyde polysaccharide being applied in medium at a concentration of at least about 0.1 weight percent to inhibit the bacterial growth.[17] Synthetic polymeric dialdehydes such as poly-(2-propenal, 2-propenoic acid) have been used in the treatment of gastrointestinal diseases. However, since the antimicrobial activities of these compounds are very weak, very high doses for treatment, such as 500˜2500 mg/kg body weight/day are required.[18]
After searching and screening it has been found that compositions including compounds of Formula (1) below, (particularly berberine chloride), and compounds of Formula (2) below, (particularly oxidized cellulose), are each useful for the treatment of the GI functional disorders and related conditions as well as for a method of promoting weight gain in animals including humans. One of the most important findings of the invention is the existence of a synergic effect obtained by using combination of the compounds of Formula (1) and compounds of Formula (2) (see Example 4 and Example 8, below). This synergic effect provides the possibility of using lower dosage of the compounds, thereby achieving higher safety and economy.